WM is a rare disease, with only about 1,500 cases per year in the United States. WM occurs more frequently in older adults.[4] While the disease is incurable, it is treatable. Because of its indolent nature, many patients are able to lead active lives, and when treatment is required, may experience years of symptom-free remission.[5]

There are genetic factors, with first-degree relatives of WM patients shown to have a highly increased risk of also developing the disease.[11] There is also evidence to suggest that environmental factors, including exposure to farming, pesticides, wood dust, and organic solvents, may influence the development of WM.[12]

Genetics

Although believed to be a sporadic disease, studies have shown increased susceptibility within families, indicating a genetic component.[13][14] A mutation in gene MYD88 has been found to occur frequently in patients.[15] WM cells show only minimal changes in cytogenetic and gene expression studies. Their miRNA signature however differs from their normal counterpart. It is therefore believed that epigenetic modifications play a crucial role in the disease.[16]

The protein Src tyrosine kinase is overexpressed in Waldenström's macroglobulinemia cells compared with control B cells.[28] Inhibition of Src arrests the cell cycle at phase G1 and has little effect on the survival of WM or normal cells.

Pathophysiology

Symptoms include blurring or loss of vision, headache, and (rarely) stroke or coma are due to the effects of the IgMparaprotein, which may cause autoimmune phenomenon or cryoglobulinemia. Other symptoms of WM are due to the hyperviscosity syndrome, which is present in 6–20% of patients.[40][41][42][43] This is attributed to the IgM monoclonal protein increasing the viscosity of the blood by forming aggregates to each other, binding water through their carbohydrate component and by their interaction with blood cells.[44]

Diagnosis

A diagnosis of Waldenström's macroglobulinemia depends on a significant monoclonal IgM spike evident in blood tests and malignant cells consistent with the disease in bone marrow biopsy samples.[45] Blood tests show the level of IgM in the blood and the presence of proteins, or tumor markers, that are the key symptoms of WM. A bone marrow biopsy provides a sample of bone marrow, usually from the back of the pelvis bone. The sample is extracted through a needle and examined under a microscope. A pathologist identifies the particular lymphocytes that indicate WM. Flow cytometry may be used to examine markers on the cell surface or inside the lymphocytes.[46]

Chemistry tests include lactate dehydrogenase (LDH) levels, uric acid levels, erythrocyte sedimentation rate (ESR), kidney and liver function, total protein levels, and an albumin-to-globulin ratio. The ESR and uric acid level may be elevated. Creatinine is occasionally elevated and electrolytes are occasionally abnormal. A high blood calcium level is noted in approximately 4% of patients. The LDH level is frequently elevated, indicating the extent of Waldenström's macroglobulinemia–related tissue involvement. Rheumatoid factor, cryoglobulins, direct antiglobulin test and cold agglutinin titre results can be positive. Beta-2 microglobulin and C-reactive protein test results are not specific for Waldenström's macroglobulinemia. Beta-2 microglobulin is elevated in proportion to tumor mass. Coagulation abnormalities may be present. Prothrombin time, activated partial thromboplastin time, thrombin time, and fibrinogen tests should be performed. Platelet aggregation studies are optional. Serum protein electrophoresis results indicate evidence of a monoclonal spike but cannot establish the spike as IgM. An M component with beta-to-gamma mobility is highly suggestive of Waldenström's macroglobulinemia. Immunoelectrophoresis and immunofixation studies help identify the type of immunoglobulin, the clonality of the light chain, and the monoclonality and quantitation of the paraprotein. High-resolution electrophoresis and serum and urine immunofixation are recommended to help identify and characterize the monoclonal IgM paraprotein.

The light chain of the monoclonal protein is usually the kappa light chain. At times, patients with Waldenström's macroglobulinemia may exhibit more than one M protein. Plasma viscosity must be measured. Results from characterization studies of urinary immunoglobulins indicate that light chains (Bence Jones protein), usually of the kappa type, are found in the urine. Urine collections should be concentrated.

Bence Jones proteinuria is observed in approximately 40% of patients and exceeds 1 g/d in approximately 3% of patients. Patients with findings of peripheral neuropathy should have nerve conduction studies and antimyelin associated glycoprotein serology.

Treatment

There is no single accepted treatment for WM.[48] There is marked variation in clinical outcome due to gaps in knowledge of the disease's molecular basis. Objective response rates are high (>80%) but complete response rates are low (0–15%).[49] The MYD88 L265P mutation induced activation of Bruton's tyrosine kinase, the target of the drug ibrutinib.[50] In a cohort study of previously treated patients, ibrutinib induced responses in 91% of patients, and at 2 years 69% of patients had no progression of disease and 95% were alive.[51] Based on this study, the Food and Drug Administration approved ibrutinib for use in WM in 2015.[52]

But on occasion, the disease can be fatal, as it was to the French president Georges Pompidou, who died in office in 1974. Mohammad Reza Shah Pahlavi, the Shah of Iran, also suffered from Waldenström's macroglobulinemia, which resulted in his ill-fated trip to the United States for therapy in 1979, leading to the Iran hostage crisis.[57]

First-line

Should treatment be started it should address both the paraprotein level and the lymphocytic B-cells.[58]

Salvage therapy

Drug pipeline

As of October 2010, there have been a total of 44 clinical trials on Waldenström's macroglobulinemia, excluding transplantation treatments. Of these, 11 were performed on previously untreated patients, 14 in patients with relapsed or refractory Waldenström's.[67] A database of clinical trials investigating Waldenström's macroglobulinemia is maintained by the National Institutes of Health in the US.[68]

Patient stratification

Prognosis

Current medical treatments result in survival of some longer than 10 years; in part this is because better diagnostic testing means early diagnosis and treatments. Older diagnosis and treatments resulted in published reports of median survival of approximately 5 years from time of diagnosis.[1] Currently, median survival is 6.5 years.[70] In rare instances, WM progresses to multiple myeloma.[71]

The International Prognostic Scoring System for Waldenström’s Macroglobulinemia (IPSSWM) is a predictive model to characterise long-term outcomes.[72][73] According to the model, factors predicting reduced survival[74] are:

Age >65 years

Hemoglobin ≤11.5 g/dL

Platelet count ≤100×109/L

B2-microglobulin >3mg/L

Serum monoclonal protein concentration >70 g/L

The risk categories are:

Low: ≤1 adverse variable except age

Intermediate: 2 adverse characteristics or age >65 years

High: >2 adverse characteristics

Five-year survival rates for these categories are 87%, 68% and 36%, respectively.[75] The corresponding median survival rates are 12, 8, and 3.5 years.[76]

The IPSSWM has been shown to be reliable.[77] It is also applicable to patients on a rituximab-based treatment regimen.[75] An additional predictive factor is elevated serum lactate dehydrogenase (LDH).[78]

For a time, WM was considered to be related to multiple myeloma because of the presence of monoclonal gammopathy and infiltration of the bone marrow and other organs by plasmacytoid lymphocytes. The new World Health Organization (WHO) classification, however, places WM under the category of lymphoplasmacytic lymphomas, itself a subcategory of the indolent (low-grade) non-Hodgkin lymphomas.[81] In recent years, there have been significant advances in the understanding and treatment of WM.[49]

Research

One recent investigation showed that a population of cells, lacking both B-cell and plasma cell markers, has characteristics of cancer-initiating cells in Waldenström's macroglobulinemia.[82]